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WO2007123269A1 - DÉRIVÉ d'azolecarboxamide - Google Patents

DÉRIVÉ d'azolecarboxamide Download PDF

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Publication number
WO2007123269A1
WO2007123269A1 PCT/JP2007/059009 JP2007059009W WO2007123269A1 WO 2007123269 A1 WO2007123269 A1 WO 2007123269A1 JP 2007059009 W JP2007059009 W JP 2007059009W WO 2007123269 A1 WO2007123269 A1 WO 2007123269A1
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WIPO (PCT)
Prior art keywords
lower alkyl
group
aryl
alkyl
hydroxy
Prior art date
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PCT/JP2007/059009
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English (en)
Japanese (ja)
Inventor
Keizo Sugasawa
Kenichi Kawaguchi
Takaho Matsuzawa
Ryushi Seo
Hironori Harada
Akira Suga
Tomoaki Abe
Hidenori Azami
Shunichiro Matsumoto
Takashi Shin
Masayuki Tanahashi
Toru Watanabe
Original Assignee
Astellas Pharma Inc.
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Filing date
Publication date
Application filed by Astellas Pharma Inc. filed Critical Astellas Pharma Inc.
Priority to EP07742444A priority Critical patent/EP2009005A4/fr
Priority to JP2008512196A priority patent/JP5182088B2/ja
Priority to MX2008013400A priority patent/MX2008013400A/es
Priority to US12/297,275 priority patent/US8163746B2/en
Priority to CN2007800140537A priority patent/CN101426774B/zh
Priority to CA2649043A priority patent/CA2649043C/fr
Publication of WO2007123269A1 publication Critical patent/WO2007123269A1/fr

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    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D277/00—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings
    • C07D277/02—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings
    • C07D277/20—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D277/32—Heterocyclic compounds containing 1,3-thiazole or hydrogenated 1,3-thiazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D277/56—Carbon atoms having three bonds to hetero atoms with at the most one bond to halogen
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K31/00—Medicinal preparations containing organic active ingredients
    • A61K31/33—Heterocyclic compounds
    • A61K31/395—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins
    • A61K31/41—Heterocyclic compounds having nitrogen as a ring hetero atom, e.g. guanethidine or rifamycins having five-membered rings with two or more ring hetero atoms, at least one of which being nitrogen, e.g. tetrazole
    • A61K31/425—Thiazoles
    • A61K31/427—Thiazoles not condensed and containing further heterocyclic rings
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/02—Drugs for disorders of the urinary system of urine or of the urinary tract, e.g. urine acidifiers
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/08—Drugs for disorders of the urinary system of the prostate
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P13/00—Drugs for disorders of the urinary system
    • A61P13/10—Drugs for disorders of the urinary system of the bladder
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P19/00—Drugs for skeletal disorders
    • A61P19/02—Drugs for skeletal disorders for joint disorders, e.g. arthritis, arthrosis
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/02—Drugs for disorders of the nervous system for peripheral neuropathies
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P25/00—Drugs for disorders of the nervous system
    • A61P25/04—Centrally acting analgesics, e.g. opioids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P29/00—Non-central analgesic, antipyretic or antiinflammatory agents, e.g. antirheumatic agents; Non-steroidal antiinflammatory drugs [NSAID]
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P43/00—Drugs for specific purposes, not provided for in groups A61P1/00-A61P41/00
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D263/00—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings
    • C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
    • C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
    • C07D263/34—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with hetero atoms or with carbon atoms having three bonds to hetero atoms with at the most one bond to halogen, e.g. ester or nitrile radicals, directly attached to ring carbon atoms
    • C07D263/48—Nitrogen atoms not forming part of a nitro radical
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
    • C07D413/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
    • C07D413/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings directly linked by a ring-member-to-ring-member bond
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings
    • C07D417/12—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing two hetero rings linked by a chain containing hetero atoms as chain links
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D417/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00
    • C07D417/14—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and sulfur atoms as the only ring hetero atoms, not provided for by group C07D415/00 containing three or more hetero rings
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/04—Ortho-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D471/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00
    • C07D471/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, at least one ring being a six-membered ring with one nitrogen atom, not provided for by groups C07D451/00 - C07D463/00 in which the condensed system contains two hetero rings
    • C07D471/10—Spiro-condensed systems
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D487/00—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00
    • C07D487/02—Heterocyclic compounds containing nitrogen atoms as the only ring hetero atoms in the condensed system, not provided for by groups C07D451/00 - C07D477/00 in which the condensed system contains two hetero rings
    • C07D487/08—Bridged systems
    • C—CHEMISTRY; METALLURGY
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    • C07D—HETEROCYCLIC COMPOUNDS
    • C07D491/00—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00
    • C07D491/02—Heterocyclic compounds containing in the condensed ring system both one or more rings having oxygen atoms as the only ring hetero atoms and one or more rings having nitrogen atoms as the only ring hetero atoms, not provided for by groups C07D451/00 - C07D459/00, C07D463/00, C07D477/00 or C07D489/00 in which the condensed system contains two hetero rings
    • C07D491/08—Bridged systems

Definitions

  • the present invention relates to azolcarpoxamide useful as a therapeutic agent for drugs, particularly frequent urination associated with various lower urinary tract diseases including overactive bladder, urgency, urinary incontinence, lower urinary tract pain, and various diseases associated with pain. Relates to derivatives.
  • Overactive bladder is a pathological condition complaining of urgency regardless of incontinence and is usually accompanied by frequent urination and nocturia (Non-patent Document 1).
  • anticholinergic drugs are mainly used for the treatment, and some treatment results have been shown.
  • side effects such as low hemorrhage, constipation, and blurred vision are known, and there is a risk of urinary retention, which has been reported to be difficult to use for patients with prostatic hypertrophy and the elderly.
  • Nerve growth factor is one of the humoral factors collectively called neurotrophic factor, and plays an important role in the generation, differentiation and maintenance of neurons in vivo.
  • NGF receptors are known to be high-affinity trkA receptors (receptor-type tyrosine kinases) and low-affinity p75 receptors. p75 binds to all neurotrophic factors and has been reported to be involved in apoptosis during the development of neurons, but its role has not been fully elucidated.
  • NGF and trkA receptor knockout mice are known to show similar phenotypes (Non-patent Document 1), and the physiological actions of NGF are thought to be expressed mainly through the trkA receptor. ⁇
  • Non-Patent Document 2 It is known that patients with overactive bladder and interstitial cystitis have elevated NGF levels in the bladder (Non-Patent Document 2), and that intravesical infusion of NGF reduces rat bladder capacity, It has been reported that NGF inhibition improves micturition function in pollakiuria model rats (Non-patent Document 3). For patients with interstitial cystitis NGF inhibition has been reported to improve frequent urination and urinary incontinence (Non-patent Document 4), so trkA receptor inhibitors are often associated with frequent urination / urinary urgency, urinary incontinence, stroma It is thought to be useful as a therapeutic agent for lower urinary tract diseases such as '14 cystitis and prostatitis.
  • trkA receptor inhibitors since the mechanism of action of trkA receptor inhibitors is different, it can be expected to avoid the side effects peculiar to anticholinergic drugs, and it can also be expected to be effective for patients who do not show efficacy with anticholinergic treatment. . In addition, this drug acts on sensory nerves and can be expected to have a stronger effect of improving subjective symptoms. Furthermore, it has been reported that the urination pressure of the frequent urine model rats is improved without reducing the urination pressure (Non-patent Document 5), and it can be expected that it can be safely administered to patients with prostatic hypertrophy and the elderly.
  • NGF inhibition has been shown to be effective in model animals such as neuropathic pain and inflammatory pain such as the sciatic nerve injury-induced pain model (Non-patent document 6) and knee joint injury-induced pain model Patent document 7), and the trkA receptor Inhibitors are thought to be useful as therapeutic agents for various pains such as lower urinary tract diseases accompanied by lower urinary tract pain and osteoarthritis.
  • Non-patent Document 8 a windrorubazole derivative
  • Patent Document 1 a pyrrolocarbazole derivative
  • Patent Document 2 a pyrazolone derivative
  • Patent Document 3 and 4 an oxindole derivative
  • Patent Document 5 Zaxindole derivatives
  • Patent Document 6 pyrazolyl fused ring compounds
  • Patent Documents 7 and 8 pyrazole derivatives
  • Patent Document 9 tricyclic derivatives
  • ALE-0540 Patent Document 1 0
  • Non-Patent Document 8 and Patent Documents 1 to 10 compounds represented by the following general formula (XV) in Patent Document 11 as c-fnis kinase inhibitors are relatively similar in structure.
  • the trkA receptor inhibitory action according to the present invention is not mentioned at all.
  • the second place is for compounds having a substituted thiazole or oxazole skeleton, there is no specific disclosure by Examples and others.
  • A is each optionally substituted phenyl, naphthyl, biphenyl; or each is optionally substituted, each having 1 to 4 from N, O or S, 5 to 7 members.
  • W may each be substituted phenyl, naphthinole, biphenyl; or each may be substituted, Each represents 1 to 4, 5 to 6-membered monocyclic or 8 to 10-membered bicyclic heterocyclic group or aromatic heterocycle having 1 to 4 from 1 ⁇ , O or S. Details Refer to the relevant bulletin for
  • Non-Patent Document 1 "Reviews iii the Neurosciences” (UK), 1997, Vol. 8, ⁇ .13 ⁇ 27
  • Non-Patent Document 2 "British Journal of Urology J, (UK), 1997, 79th, ⁇ .572 / 7
  • Non-Patent Document 3 "Neuroscience” (USA), 1997, Vol. 78, No. 2, p.449-59
  • Non-patent literature 6 "Pain”., (USA), 1999, Vol. 81, p.245-55
  • Non-patent literature 7 "Pain”, (USA), 2005, 116, p.8-16
  • Non-Patent Document 8 "Cancer Research", 1999, No.
  • Patent Document 1 International Publication Pamphlet WO01 / 14380
  • Patent Document 2 Internationally published pamphlet WO01 / 32653
  • Patent Document 3 Internationally published pamphlet WO02 / 20479
  • Patent Document 4 Internationally published pamphlet WO02 / 20513
  • Patent Document 5 International Publication Pamphlet WO03 / 027111
  • Patent Document 6 Japanese Patent Laid-Open No. 2003-231687
  • Patent Document 7 International Publication Pamphlet WO2005 / 049033
  • Patent Document 8 International Publication Pamphlet WO2005 / 103010
  • Patent Document 9 International Publication Pamphlet WO2005 / 076695
  • Patent Document 1 International Publication Pamphlet WO01 / 78698
  • Patent Document 1 International Publication Pamphlet WO2004 / 096795
  • trkA receptor inhibitors are expected to be highly safe lower urinary tract diseases and therapeutic agents with few side effects such as phlegm and urinary retention. Therefore, the present inventors have aimed to provide a novel compound useful for the treatment of lower urinary tract diseases, etc.
  • the present invention relates to a novel azolecarboxamide derivative represented by the following general formula (I) or a salt thereof.
  • A optionally substituted phenylene, optionally substituted pyridine diyl, optionally substituted pyrimidine dil, optionally substituted thiophene dizyl, optionally substituted virazole dil or optionally substituted pyridone dil
  • Q A monocyclic or bicyclic alicyclic nitrogen-containing heterocyclic group which may be substituted
  • R1 a nonogen, a lower alkylcarbonyl, an optionally substituted Ci—C 7 alkyl, an optionally substituted lower cycloalkyl, an optionally substituted lower alkoxy, an optionally substituted aryl, or an optionally substituted Good heteroaryl, general formula
  • Rla, Rib each independently 1 H, optionally substituted lower alkyl, lower Cycloalkyl, optionally substituted hetero-saturated cyclic group, lower alkyl carbonyl, lower alkoxycarbonyl, vinyl or heteroaryl,
  • Ric 1 H or lower alkyl
  • Rid —H, lower alkyl, lower alkylcarbonyl, lower alkoxycarbonyl or aryl lower alkyl,
  • Y 2 Lower alkylene, and between the carbons, 1——, S—, 1 S0 2 —, 1 N (_Rie) —, — N (—CO—R lf ) —, —N (—CO-NH -Rig) One, one N (— CS-NH-Rig) — or — N (—S0 2 -R lh ) — may be included,
  • Rie —H or optionally substituted lower alkyl
  • Rlf may be substituted, lower alkyl, lower alkyl, lower alkoxy, optionally substituted aryl, optionally substituted heteroaryl or aryl lower alkenyl,
  • R! G 1H, lower alkyl, aryl or aryl lower alkyl
  • R lh lower alkyl, lower cycloalkyl, lower cycloalkyl lower alkyl, optionally substituted aryl, heteroaryl or aryl lower alkyl
  • R 2 — H, halogen or nitrogen-containing hetero saturated ring group. The same applies below.
  • the compound of the present invention has a potent trkA receptor inhibitory action, urination symptom improving action, and analgesic action, for example, frequent urination associated with various lower urinary tract diseases including overactive bladder, urgency, urine It is useful as a therapeutic or preventive for incontinence, various lower urinary tract diseases with lower urinary tract pain such as interstitial cystitis and chronic prostatitis, and various diseases with pain.
  • various lower urinary tract diseases with lower urinary tract pain such as interstitial cystitis and chronic prostatitis, and various diseases with pain.
  • the compound of the present invention has a different mechanism of action from anticholinergic drugs, it can be expected to be effective even in patients who do not show efficacy with anticholinergic treatment, and safety that avoids side effects peculiar to anticholinergic drugs It can be expected to be a highly therapeutic agent for lower urinary tract disease. [Best Mode for Carrying Out the Invention]
  • lower means a straight or branched carbon chain having 1 to 6 carbon atoms (hereinafter abbreviated as d- 6 ) unless otherwise specified.
  • “lower alkyl” is Cl- 6 alkyl, preferably linear alkyl such as methyl, ethyl, n-propyl, and n-butyl, and propyl, isobutyl, tert-butyl, neopentyl, and the like. Branched alkyl.
  • Ci-4 alkyl is more preferred, and methyl, ethyl, n-propyl, isopropyl and tert-butyl groups are particularly preferred.
  • “Lower alkylene” is a divalent group of Ci- 6 alkyl, preferably Cr 3 alkylene, methylene, ethylene, methylmethyle.
  • “Lower alkoxy” means 1 O-lower alkyl, preferably Cl-4 alkoxy, particularly preferably methoxy, ethoxy, and tert-butoxy.
  • halogeno lower alkyl means a Ci-6 alkyl substituted with one or more halogen, preferably CI- 6 alkyl substituted with one or more F, C1, more preferably, black Oral propyl, fluorethyl, trifluoromethyl, trifluoroethyl and trifluoropropyl groups.
  • cycloalkyl C 3 - 10 saturated hydrocarbon ring group, which may have a bridge.
  • C 3 - a 8 cycloalkyl particularly preferably cyclohexyl group cyclopropyl, Shikuropuchinore, cyclopentyl and consequent opening.
  • the "Ariru”, C 6. 14 is a monocyclic to tricyclic aromatic hydrocarbon ring group, good Mashiku is phenyl and naphthyl groups. More preferred is phenyl.
  • the aryl may be condensed with a monocyclic oxygen-containing saturated heterocyclic ring or a monocyclic alkyl ring.
  • “Aryl Lower Alkynore”, “Aryl Lower Alkenyl”, “Aryloxy”, “Aryl Lumino” and “Aryl Carbonyl” Meaning “lower alkyl substituted by aryl”, “lower alkyl substituted by aryl”, “oxyl substituted by aryl”, “amino substituted by aryl” and “carbonyl substituted by aryl” respectively. .
  • Heteroaryl means a 5- to 8-membered, preferably 5- to 6-membered monocyclic aromatic ring group containing 1 to 3 heteroatoms selected from 0, S and N (monocyclic heterocycle). And a monocyclic heteroaryl, a benzene ring and a monocyclic heteroaryl, or a bicyclic or tricyclic heteroaryl fused with a benzene ring and a heterocycle.
  • Monocyclic heteroaryl is preferably pyridyl, pyridadiel, pyrimidinyl, pyrazinyl, pyrrolyl, imidazolyl, triazolyl, chenyl, furyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl group, preferably oxadiazolyl group, Examples include pyridazinyl, pyrimidinyl, pyrajyl, pyrrolyl, chenyl, and furyl groups.
  • Preferred examples of the bicyclic heteroaryl include dihydrobenzo fullerel. '
  • heteroaryl which is a ring atom, may be oxidized to form an oxide by oxidizing an oxide or dioxide, or N.
  • Heteroaryl lower alkyl means “lower alkyl substituted by heteroaryl”.
  • heterosaturated ring group a 4- to 8-membered, preferably 5- to 6-membered hetero-saturated ring group containing one N or O heteroatom, one N atom, and N, A 5- to 8-membered hetero-saturated cyclic group containing one hetero atom consisting of 0 and S.
  • Preferred are azetidinyl, pyrrolidinyl, piperidyl, azepanyl, piperazil, diazepanyl, tetrahydrofuranyl, tetrahydrobiranyl, morpholinyl, oxazepanyl and thiomorpholinyl groups.
  • hetero-saturated ring S, which is a ring atom, may be oxidized to form oxide or dioxide, or N may be oxidized to form oxide.
  • the “alicyclic hetero ring group” refers to the hetero saturated ring group or a heterocyclic group having a double transition in the structure thereof.
  • “Monocyclic or bicyclic alicyclic nitrogen-containing heterocyclic group” means a saturated or partially unsaturated 4- to 8-membered, preferably 5- to 6-membered monocyclic nitrogen-containing heterocyclic group and A 4- to 8-membered, preferably 5- to 6-membered nitrogen-containing heterocyclic group having one bridge. More preferably, they are azetidinyl, pyrrolidyl, piperidyl, azepanyl, piperazinyl, diazepanyl, morpholinyl, thiomorpholinyl, 2,5-diazabixic heptyl, and tetrahydropyridyl groups.
  • R 3 1 H, halogen, lower alkyl, cyan, cyan lower alkyl, hydroxy lower alkyl, lower alkoxy, halogeno lower alkoxy, lower alkoxy lower alkyl, lower alkenyl, cyan lower alkenyl, carboxy, rubamoinole, lower alkoxy Carbonyl, carboxy lower alkyl, lower alkoxycarbonyl lower alkyl, carbamoyl lower alkyl, lower alkylaminocarbonyl lower alkyl, lower alkylsulfonyl, aminosulfonyl or lower alkylsulfur,
  • R4 _H, halogen or lower alkoxy
  • R 3 and R 4 may be combined and bridged as 10-lower alkylene
  • R5 —H or halogen
  • R6 1 H or lower alkyl. The same applies below. ) 3) More preferably, 2) the compound wherein A is a divalent group represented by the following formula.
  • R23a hydroxy, amino, tert-butylamino, methoxy or ethoxy
  • R24 — H, fluoro, black mouth, bromo or methoxy
  • R 23 and R 24 may be combined together and crosslinked as 1-O-ethylene,
  • R25 —H or bromo
  • V2 Independently, ⁇ 3 alkylene
  • V3 methylene or ethylene
  • W _CH (— R9) —, _N (_R9) _, 1 O—, 1 S—, SO— or — SO
  • R 7 and R 8 each independently — H, halogen, hydroxy, lower alkyl, hydroxy lower alkyl, carboxy, lower alkoxycarbonyl, lower alkyl carbonyloxy, rubamoyl, aryl, aryl lower alkyl, lower A hetero-saturated cyclic group which may be substituted with alkyl, or an —A 1 k-hetero-saturated cyclic group,
  • R 7 , R 8 and R 9 may be combined together and bridged as lower alkylene.
  • R7 ⁇ Pi R 8 may be substituted on the same carbon atom, taken together, a Okiso group May form a spiro-bonded nitrogen-containing heterosaturated ring group, wherein the nitrogen-containing heterosaturated ring group may be substituted with a lower alkyl or oxo group,
  • R9 H, lower alkyl, cyan, hydroxy, lower alkoxy, lower alkenyl, lower alkoxycarbonyl lower alkenyl, lower alkylsulfonyl, -A 1 k—R9a, 1 CO 1 R9b, -A 1 k—CO One R9b, _ CO One A 1k
  • R9a Siano, hydroxy, lower alkoxy, mono- or dihydroxy lower alkyl, aryl, aryloxy, aryl carboninoleoxy, an amino optionally substituted with lower alkyl, lower alkoxycarbonylamino, heteroaryl or hetero
  • a saturated ring group wherein the heteroaryl may be substituted with a lower alkyl or oxo group, and the heterosaturated ring group may be substituted with a lower alkyl group,
  • RSb lower alkyl, hydroxy, lower alkoxy, —NR 9 fR 9 g or alicyclic heterocyclic group, where the alicyclic heterocyclic group is lower alkyl, hydroxy, carboxy, lower alkoxycarbonyl, mono or Di-lower alkylamino, optionally substituted with a hetero-saturated ring group or —A 1 k-hetero-saturated ring group,
  • R 9 f and R 9 g each independently, 1 H, lower alkyl, hydroxy lower alkyl, optionally substituted with amino, lower alkyl, lower alkoxy lower alkyl, mono or di lower alkylamino lower Alkyl, lower alkylsulfonyl, heteroaryl, heterosaturated ring group,
  • hetero-saturated cyclic group may be substituted with lower alkyl or aryl lower alkyl.
  • a 1 k heterosaturated cyclic group
  • a 1 k _ lower alkylene
  • R 9c lower alkoxy, lower alkylcarbonyloxy or hetero-saturated ring, wherein the hetero-saturated ring group may be substituted with lower alkyl or oxo group,
  • R 9 e each independently — H, lower alkyl, lower alkyl carbonyl
  • R27 and R28 each independently, at first, fluoro, hydroxy, oxo, methinore, hydroxymethinore, carboxy, rubamoyl, acetooxy, methoxycarboninole, fenenore, benzinore, pyrrolidinoremethyl, or methyl
  • fluoro fluoro
  • hydroxy, oxo methinore
  • hydroxymethinore carboxy
  • rubamoyl acetooxy
  • methoxycarboninole fenenore
  • benzinore benzinore
  • pyrrolidinoremethyl or methyl
  • optionally substituted piperidyl
  • R27 ⁇ Pi R 28 are together attached to the same carbon atom constituting the ring of Q, Spiro bonds may be formed by forming a pyrrolidine ring that may be substituted with methyl and oxo.
  • R 29 Piperidyl optionally substituted with H, hydroxy, cyano, methinole, ethyl, isopropyl, isopentyl, aryl, methoxy, methoxycarbonylaryl, ethoxycarbonylaryl, fuel, phenoxy, methyl group , 'Piperazinyl optionally substituted with a methyl group or oxo group, morpholinyl, methylsulfonyl, tetrahydrofuryl optionally substituted with hydroxy, one A 1 k one R29a, one CO—R29b, -A 1 k one CO — R29b, -CO-A 1k -R29c or one N R29dR29e,
  • a 1 k— methylene, ethylene, methenolemethylene, trimethylene, tetramethylene or pentamethylene,
  • R29a methoxy, cyano, hydroxy, phenenole, phenoxy, benzoinoxy, pyridyl, thiazolyl, oxazolyl, oxadiazolyl, trioxolyl which may be substituted with oxo, imidazolyl which may be substituted with methyl, substituted with methyl Pyrrolidinyl, which may be substituted with methyl, piperidyl, morpholinyl, oxazepanyl, 1,2-dihydroxyethyl, 1-hydroxypropyl, amino, dimethinoreamino, jetinoreamino, tert-butoxycanepononoleamino,
  • R29b methyl, human Dorokishi, main butoxy, ethoxy, butoxy, which may have a substituent selected Ri by the following groups pyrrolidinyl, pyrrolinyl, which may have a substituent group selected from the following G 5-2 groups good piperidyl, following G 5 - 3 piperazinyl which may have a selected Ru substituents from the group, which may be substituted by methyl Jiazepa Nino V, morpholin lambda ⁇ Tetorahi Dorobiraniru or one N R29fR29g,
  • R29f 1H, methyl, ethyl, hydroxyethyl, methoxetyl, tetrahydroviranyl, morpholino reethinole, dimethinoreaminoethyl, mesinole, pyridyl, amino optionally substituted cyclohexyl, methyl in unsubstituted or may piperidyl or below
  • G 5 are - 4 may have a substituent group selected from the group pyro lysinyl, R29g: - H, methyl or Echiru,
  • G 5 - 4 groups methyl ⁇ Pi benzyl
  • R 29 c methoxy, acetooxy, pyrrolidinyl, piperazinyl optionally substituted with methyl, morpholyl, or thiomorpholinino which optionally substituted with oxo,
  • R 29d and R 29e each independently 1 H, methyl, ethyl, acetyl, or force Norepamoinoremethinore.
  • Ri halogen, lower alkylcarbonyl, lower alkyl which may be substituted with hydroxy, lower alkoxy which may be substituted with lower alkoxy, which may have a substituent selected from the following group 7 alkyl, aryl, heteroaryl, a group represented by the general formula (X), (X 1), (XI 1), (XIII) or (XIV),
  • G 6 - may have 2 1 ⁇ optimum 2 substituents selected from the group, two substituents may form a cyclic structure together ,
  • aryl or aryloxy may be substituted with a halogen or a halogeno lower alcohol.
  • G 6 - 2 groups halogen, hydroxy, old Kiso, lower alkyl, halogeno-lower alk kill, lower alkoxy, Shiano, carboxy, force Rubamoiru ⁇ Pi one NR ii R 1], R u and Ri] ': each independently , 1 H, lower alkyl, lower alkoxy lower alkyl or lower alkoxycarbonyl, [Chemical 20]
  • Rlp, RLQ each independently one of H, lower cycloalkyl, lower alkyl force Noreboniru, lower alkoxy Kano levo sulfonyl, ⁇ Li one Honoré, Heteroariru, saturated hetero ring group, or the following G 6 - is selected from the three groups A lower alkyl which may have a substituent,
  • the hetero-saturated ring group may have a substituent selected from the group consisting of a lower alkyl which may be substituted with 1 to 2 aryls and an aryl lower alkoxycarbonyl.
  • G 6-3 group halogen, hydroxy, cyan, lower alkoxy, lower alkoxy lower alkoxy, aryl, heteroaryl, hetero saturated cyclic group, carboxy, lower alkoxycarbonyl, lower alkylsulfanyl, lower alkylsulfuryl, lower alkylsulfonyl, lower Carbamoyl optionally substituted with alkyl and Richi R 11,
  • Rik and Rii each independently 1 H, lower alkyl, lower alkyl carbonyl, lower alkoxycarbonyl or lower alkylsulfonyl, k: 0, 1 or 2,
  • Y3 single bond, one CH 2 —, _0—, one N (-R LM ) one, one S—, one SO— or one so 2 —,
  • Rim — H, lower alkyl, lower alkylcarbonyl, lower alkoxycal Ponyl or aryl lower alkyl,
  • R Rls each independently — H, halogen, hydroxy, lower alkyl, lower alkoxy, hydroxy lower alkyl, lower alkoxy lower alkyl, lower alkylcarbonyloxy, carboxy, lower alkoxycarbonyl, carpamol, mono or di lower alkylamino Lower alkyl, aryl or
  • n 0, 1 or 2
  • n 2 or 3.
  • Riu ⁇ ⁇ , lower alkyl, One A LK RIW, One CO- Rix one S0 2 - or a single CS-NH- Ri z,
  • Riw lower cycloalkyl, lower alkoxy, carboxy, rubamoyl, hetero saturated ring group, aryl, heteroaryl,
  • the aryl may have a substituent selected from the group consisting of lower alkyl, lower alkoxy and carboxy group,
  • R lx lower alkyl, lower cycloalkyl, hydroxy lower alkyl, lower alkoxy, lower alkoxy lower alkyl, amino, lower alkylamino, Rylamino, aryl lower alkylamino, mono- or dilower alkylamino lower alkyl, aryl, halo
  • the aryl or heteroaryl may have a substituent selected from the group consisting of halogen, lower alkyl, lower alkoxy and aryl.
  • Riy lower alkyl, lower cycloalkyl, lower cycloalkyl lower alkyl, aryl, aryl lower alkyl, heteroaryl,
  • aryl has a substituent selected from the group consisting of halogen and aryl.
  • Riv —H or lower alkoxycarbonyl
  • G 7 - 2 may be substituted with 1 or 2 groups selected from the group, G 7 - 2 groups: Furuoro, black hole, bromo, hydroxy, Okiso, methyl, triflumizole Ruoromechiru, main butoxy , Cyano, carboxy, canolemoyl, amino, methylamino, dimethylamino, methoxetyl (methyl) amino and tert-butoxycarbonylamino,
  • Riip 1H, methinole, ethyl, propyl, isopropyl, cyclbutinole, trifluoroethyl or methoxetyl,
  • Riiq —H, Cyclup pill, Cycleptyl, Acetyl, tert-Butoxycarbonyl, Phenyl, Pyridyl, Tetrahydrobiranyl, Tetrahydrofuryl, Oxetanyl, Pyrrolidinyl, Methylpyrrolidinyl, Benzyloxycarbonylpyrrolidinyl, Diphenylmethyl Azechijuru, or following G 7 - one may have a third group by Ri substituent selected C 4 alkyl,
  • G 7 - 3 groups Funoreo port, black hole, hydroxy, Shiano, main butoxy, ethoxy, main Tokishietokishi, Amino, Mechiruamino, Jimechiruamino, Asechiruamino, Meshiruamino, tert- butoxycarbonyl ⁇ amino, carboxy, Karupamoi Le, Jimechiruamino Carbonyl, methoxycarbonyl, phenyl, pyridyl, frinole, tetrahydrofuryl, methylthio, methylsulfinyl and mesyl,
  • the morpholinyl, following G 7 - may have a substituent selected from 4 group,
  • G 7 - 4 groups methyl, hydroxymethyl, main Tokishimechiru and Jimechiruaminome chill,
  • the nitrogen atom in the following G 7 - 5 may be substituted a group selected from the group, the following G 7 - may have a substituent group selected from group 6,
  • G 7 - 5 groups methyl, propyl, Asechiru, benzyl or tert- butoxycarbonyl two Le,
  • G 7 - 6 groups Funoreo port, hydroxy, hydroxymethyl, main butoxy, main Tokishime chill, old Kiso, Mechiruamino or phenyl,
  • the piperidyl represented by the following G 7 - may be substituted with 1 or 2 groups selected from seven groups,
  • G 7 - 7 group Furuoro, hydroxy, human Dorokishimechiru, main butoxy, ethoxy, Acetyloxy, Taxo, Carboxy, Carpamoinole, Ethoxycarboninole, Hydroxypropylcarpamoyl or Tetrahydrofurinolemethylcarbamoyl,
  • G 7 - may be substituted with 1 or 2 groups selected from group 8, G 7 - 8 groups: Furuoro, hydroxy, hydroxymethyl, main butoxy, main Tokishime chill, Okiso, Mechiruamino Or phenyl,
  • (k) 4-Oxazepael, 4-thiomorpholinyl, 1-oxothiomorpholin-4-yl, 1,1-dioxothiomorpholin-4-yl, 2,5-diazabicycloheptane-1- , 2-oxa-5-azabisic mouth [2.2.1] heptane-5-inole, tetrahydrofuryl, tetrahydrobiranyl, thiazic hexyl, or 1,1-dioxothiax hexinole,
  • R2i t —H or methyl
  • a 1 k— Methylene, ethylene, trine, Ding: nantamethylene, methinoret trimethylene, R 21w; -H s cyclopropyl, methoxy, carboxy, strong rubamoyl, tetrahydrofuryl, pyridyl or phenyl,
  • the funinole may have a substituent selected from the group consisting of methyl, methoxy and carboxy.
  • R21x methyl, ethynole, propyl, butyl, pentyl, isopropyl, ethylpropyl, cyclobutyl, cyclopentyl ⁇ /, cyclohexyl, pyrrolyl optionally substituted with methyl, pyridyl, pyridazinyl, pyrimidinyl, phenyl, phenyl, tert-butoxy, amino, isopropinoleamino, phenylamino or benzylamino, phenylbiphenyl, phenylpropenyl, or one A 1 where the phenylole is selected from the group consisting of fluoro, methyl, methoxy and phenyl May have a substituent,
  • a 1 k 3ix- methylene, ethylene, trimethylene or tetramethylene,
  • R 31x hydroxy, methoxy, dimethylamino, phenyl or pyridyl optionally substituted by fluoric mouth,
  • R2iy methyl, ethynole, propyl, ptyl, isopropyl, cyclopropyl, cyclohexenole, cyclohexolemethinole, feninole, benzinole, fenenoreethyl, or chenil,
  • vinylate may have a substituent selected from the group consisting of fluoro and phenyl,
  • R 2 — H, halogen or nitrogen-containing hetero saturated ring group.
  • R 2 is a group shown below.
  • R 2 —H, bromo or pyrrolidinyl group.
  • the permissible substituent of the word “may be substituted” may be any substituent that is usually used as a substituent of each group, and one or more substituents in each group You may have.
  • Examples of the substituent of “optionally substituted phenylene, optionally substituted pyridine diyl or optionally substituted pyrimidine diyl” in A of the general formula (I) include halogen, lower alkyl, cyano and cyano lower alkyl.
  • the two substituents may be bridged together as a mono-O-lower alkylene, “optionally substituted thiopheneyl, optionally substituted pyrazole diyl or substituted, in A of general formula (I)
  • substituents of “good pyridonyl” include halogen and lower alkyl.
  • the substituent of “optionally substituted monocyclic or bicyclic alicyclic nitrogen-containing heterocyclic group” in Q of general formula (I) includes halogen, hydroxy, oxo, cyan, lower alkyl, Lower alkenyl, Lower alkoxycarbonyl Lower alkenyl, Lower alkyl strength Rubonyloxy, Lower alkyl sulfole, aryl, aryloxy, hetero saturated cyclic group, 1 A lk—R9a, 1 CO _ R9b, -A 1 k
  • hetero-saturated ring group may be substituted with a lower alkyl, hydroxy or oxo group, and may be spiro-bonded.
  • R 9a a cyano, hydroxy, lower alkoxy, mono or dihydroxy lower alkyl, aryl, aryloxy, arylcarbonyloxy, an amino, heteroaryl or hetero-saturated cyclic group which may be substituted with a lower alkyl,
  • the heteroaryl may be substituted with a lower alkyl or oxo group, and the hetero saturated ring group may be ft-substituted with a lower alkyl
  • RSb lower alkyl, hydroxy, lower alkoxy, alicyclic heterocyclic group or
  • alicyclic heterocyclic group is a lower alkyl, hydroxy, force alkoxy, lower alkoxy carbo, mono- or di-lower alkylamino, hetero-saturated ring group or one A 1 k mono-hetero-saturated ring.
  • R9f and R9g each independently, lower alkyl, hydroxy lower alkyl, lower cycloalkyl optionally substituted with amino, lower alkoxy lower alkyl, mono- or di-lower alkylamino lower alkyl, lower alkylsulfonyl, heteroaryl A hetero saturated ring group,
  • hetero saturated ring group may be substituted with lower alkyl or aryl lower alkyl.
  • R9c lower alkoxy, lower alkylcarbonyloxy or hetero-saturated ring group, and the hetero-saturated ring group may be substituted with lower alkyl or oxo.
  • R 9d and R 9e each independently — H, lower alkyl, lower alkyl carbonyl, or rubamoyl lower alkyl.
  • Substituents for “optionally substituted C—C 7 alkyl” in R 1 of the general formula (I) include hydroxy, lower alkoxy, N-lower alkyl 1 N-lower alkoxy lower alkylamino, mono- or di-lower alkyl, / Realkylamino, heterosaturated ring group, aryl and aryloxy.
  • aryl or aryloxy may be substituted with halogen or halogeno lower alkyl
  • Examples of the substituent of “optionally substituted lower cycloalkyl” in R 1 of the general formula (I) include hydroxy.
  • Examples of the substituent of “lower alkoxy which may be substituted” in R 1 of the general formula (I) include lower alkoxy.
  • the substituents of “optionally substituted aryl” and “optionally substituted heteroaryl” in R 1 of the general formula (I) include halogen, hydroxy, oxo, lower alkyl, halogeno lower alkyl, lower alkoxy , Siano, force ruboxy, force rubamoinole and one NR "R.
  • R ′ each independently 1 H, lower alkyl, lower alkoxy lower alkyl or lower alkoxy cananolonyl.
  • Substituents of “optionally substituted lower alkyl” in Ria and Rib of the general formula (II) include halogen, hydroxy, cyan, lower alkoxy, lower alkoxy lower alkoxy, aryl, heteroaryl, heterosaturated ring group, Examples include carboxy, lower alkoxy carboyl, lower alkyl sulfanyl, lower alkyl sulfier, lower alkyl sulfonyl, and power rubamoyl optionally substituted with lower alkyl and N RikRU.
  • Rik and RU each independently 1 H, lower alkyl, lower alkyl carbonyl, lower alkoxycarbonyl or lower alkyl sulfol.
  • Examples of the substituent of “optionally substituted hetero saturated ring group” in Ria and Rib of the general formula (II) include lower alkyl and aryl lower alkoxycarbonyl which may be substituted with aryl. .
  • Substituents for “optionally substituted lower alkylene” in Y of general formula (III) include halogen, hydroxy, oxo, lower alkyl, lower alkoxy, hydroxy lower alkyl, lower alkoxy lower alkyl, aryl, and aryl.
  • two substituents may be combined together to form a lower alkylene, and the two substituents may be substituted with the same carbon atom.
  • Rln Hydroxy or hetero saturated ring group.
  • Examples of the substituent of the “optionally substituted lower alkyl” of Rle in Z of the general formula (IV) include lower cycloalkyl, lower ananoloxy, carboxy, carbamoyl, .heterosaturated cyclic group, aryl and heteroaryl.
  • the aryl may have a substituent selected from the group consisting of lower alkyl, lower alkoxy and carboxy group,
  • substituents of “optionally substituted lower alkyl” of Rif in Z of formula (IV) include hydroxy, lower alkoxy, mono- or di-lower alkylamino, aryl and heteroaryl which may be substituted with halogen. It is possible. '
  • substituents of “optionally substituted aryl” and “optionally substituted heteroaryl” of Rif in Z of the general formula (IV) include halogen, lower alkyl, lower alkoxy and aryl.
  • Examples of the substituent of “optionally substituted aryl” of Rih in Z of the general formula (IV) include halogen and aryl.
  • the compound of the present invention represented by the general formula (I) may contain an asymmetric carbon atom depending on the kind of the substituent, and optical isomers based on this may exist.
  • the present invention includes all of these optical isomers and isolated ones.
  • the compounds of the present invention may have tautomers, but the present invention includes separated or mixtures of these isomers. Examples of such a tautomer include a tautomer between 2-hydroxypyridine and 2-pyridone.
  • the present invention includes a label, that is, a compound in which one or more atoms of the compound of the present invention are substituted with a radioactive isotope or a non-radioactive isotope.
  • the present invention includes a “pharmaceutically acceptable prodrug” relating to the compound represented by the general formula (I).
  • “Pharmaceutically acceptable prodrug” refers to C0 2 H, NH 2 , OH, etc. by solvolysis or under physiological conditions. It is a compound that produces the compound (I) of the present invention by conversion to a group.
  • groups that form prodrugs include groups described in Prog. Med., 5, 2157-2161 (1985) and “Development of pharmaceuticals” (Yodogawa Shoten, 1990) VII Molecular Design 163-198 .
  • the salt of the compound (I) of the present invention is a pharmaceutically acceptable salt, specifically, an inorganic acid such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, Formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumanoleic acid, maleic acid, lactic acid, malic acid, tartaric acid, citrate, methanesulfonic acid, ethanesulfonic acid, aspartic acid, glutamic acid, etc. And acid addition salts with organic acids. Depending on the type of the substituent, a salt with a base may be formed.
  • an inorganic acid such as hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid, phosphoric acid, Formic acid, acetic acid, propionic acid, oxalic acid, malonic acid, succinic acid, fumanole
  • an inorganic base containing a metal such as sodium, potassium, magnesium, calcium, aluminum, lithium, or methylamine, ethylamine, ethanolamine.
  • salts with organic bases such as min, lysine, ornithine, and ammonium salts.
  • the compound (I) of the present invention and salts thereof include various hydrates, solvates and crystalline polymorphs.
  • the compound according to the present invention and a pharmaceutically acceptable salt thereof can be produced by applying various known synthetic methods using the characteristics based on the basic skeleton or the type of substituent.
  • the typical production method is illustrated below.
  • the protective group can be removed as necessary to obtain the desired compound.
  • Examples of such a functional group include a hydroxyl group, a forcel loxyl group, an amino group, and the like.
  • Examples of protective groups for these functional groups include Protective Groups in Organic by TW Greene and RGM Wuts.
  • the desired compound can be obtained by removing the protective group or converting to a desired group as necessary.
  • the prodrug of compound (I) or a salt thereof can be produced by introducing a specific group at the raw material or intermediate stage, or reacting with the obtained compound (I), as in the case of the protecting group. .
  • the reaction can be carried out by applying methods known to those skilled in the art, such as ordinary esterification, amidation, and acylation.
  • This step is a step for producing compound (I) by amidating compound (2) or a reaction derivative thereof with compound (1) or a salt thereof by a conventional method and removing a protecting group as necessary. .
  • Examples of reactive derivatives of compound (2) include methyl esters, ethyl esters, and tert-butyl esters; acid halides such as acid chloride and acid bromide; acid azides; 1-hydroxybenzotriazole , P-nitrophenol, active ester with N-hydroxysuccinimide, etc .; symmetric acid anhydride; halocarboxylic acid alkyl ester such as alkyl carbonate halide, piperyl halide, p-toluenesulfonic acid chloride, etc. And mixed acid anhydrides such as phosphoric acid mixed acid anhydrides obtained by reacting diphenyl phosphoryl chloride and N-methylmorpholine.
  • acid halides such as acid chloride and acid bromide
  • acid azides 1-hydroxybenzotriazole , P-nitrophenol, active ester with N-hydroxysuccinimide, etc .
  • symmetric acid anhydride halocarboxylic acid alkyl ester such as alkyl carbon
  • 1-ethyl-3- (3-dimethylamino) can be used.
  • polystyrene resin carrying a isocyanate for the purpose of removing excess amine after completion of the reaction such as PS-isocyanate.
  • polystyrene resin carrying quaternary ammonium salt for the purpose of removing excess carboxylic acid after the reaction and the above-mentioned additives such as HOBt, such as MP-Carbonate (Argonaute Technologies, USA) Etc. may be preferable.
  • the acid chloride method and the method of reacting in the presence of an active esterifying agent and a condensing agent are simple.
  • the reaction varies depending on the reactive derivative and condensing agent used, but usually halogenated hydrocarbons such as dichloromethane, dichloromethane, and chloroform; aromatic hydrocarbons such as benzene, toluene, and xylene; ether, Ethers such as tetrahydrofuran (THF); Esters such as ethyl acetate (EtOAc); Acetonitrile, N, N-dimethylformamide (DMF), N, N-dimethylacetamide (DMA), dimethyl sulfoxide (DMSO), etc.
  • halogenated hydrocarbons such as dichloromethane, dichloromethane, and chloroform
  • aromatic hydrocarbons such as benzene, toluene, and xylene
  • ether Ethers such as tetrahydrofuran (THF); Esters such as ethyl acetate (EtOAc); Acetonitrile, N, N-di
  • the compound (1) is used in excess, or N-methylmorpholine, trimethylamine, triethylamine, diisopropylethylamine, ⁇ , ⁇ -dimethylaniline, pyridine, 4- ( ⁇ , ⁇ -dimethylamino).
  • a base such as pyridine, picoline, lutidine, etc.
  • a salt composed of a weak base and a strong acid such as pyridine hydrochloride, pyridine ⁇ -toluenesulfonate, or ⁇ , ⁇ -dimethylaniline hydrochloride may be used.
  • Pyridine can also be used as a solvent.
  • reaction is preferably carried out in a solvent such as THF or DMF in the presence of a base such as triethylamine.
  • Z i represents halogen, SMe, SOMe, S0 2 Me, SO 3 H or OTf.
  • Li represents chlorophyll or methyl.
  • RA may be any commonly used substituent, and is preferably lower alkyl, more preferably lower alkoxy lower alkynole.
  • Yl, Rla and Rib each have the same meaning as described above. Less than Same. )
  • the nucleophilic substitution reaction in this step is carried out by reacting compound (3) with halogenated hydrocarbons, aromatic hydrocarbons, ethers, esters, alcohols such as methanol, ethanol, and isopropanol, acetonitrile, DMF, Inactive in the reaction of DMA, DMSO, etc. 1.
  • Organic bases such as triethylamine, disopropylethylamine, and Z or carbonated lithium, sodium carbonate, cesium carbonate, sodium hydrogen carbonate, hydrogen in raw organic solvents It can be carried out by reacting compound (4), (5) or HO-RiA in the presence of an inorganic base such as sodium chloride.
  • a catalyst such as dimethylaminopyridine may be added.
  • the compound (4) or (5) may be used in excess.
  • the reaction varies depending on the base used, but can be carried out under cooling to room temperature, from room temperature to heating, or from room temperature to reflux.
  • polystyrene resin carrying isocyanate for the purpose of removing excess amine after completion of the reaction, such as PS-isocyanate.
  • the 1,3-dipolar cycloaddition reaction in this step is a reaction in which compound (6) is cycloadded with azomethine ylide generated in the system.
  • organic solvent inert to the reaction such as ethers, esters, acetonitrile, DMF, DMA, DMSO, organic acids such as trifluoroacetic acid, or trimethylsilanol trifluoromethanesulfonate, cesium fluoride, lithium fluoride, It can be carried out by reacting the compound (6) in the presence of a Lewis acid such as tetraptyl ammonium fluoride or zinc chloride.
  • the reaction varies depending on the acid and solvent to be used, but can be carried out under cooling to room temperature, from room temperature to heating, or from room temperature to reflux.
  • the compound of the present invention having various functional groups represented by the formula (I) is prepared from the compound of the present invention obtained by the first production method, the second production method, or the third production method by known alkylation, acylation, substitution reaction. It can be produced by arbitrarily combining processes that can be usually employed by those skilled in the art, such as oxidation, reduction, and hydrolysis. This process is not limited to a one-step reaction and may be composed of a multi-step reaction. In addition, these steps that can be usually employed by those skilled in the art are not limited to application to the compound of the present invention, but can also be applied to production intermediates.
  • the compound having an amide group reacts with amine by reacting a compound having an amino group with a carboxylic acid and a reactive derivative thereof as a raw material, or with a compound having a carboxylic acid as a raw material.
  • the reaction is in accordance with step A of the first production method, for example, “Experimental Chemistry Course (4th edition)” 22 ⁇ (1992) (Maruzen) or “Compendium of Organic Synthetic Methods”, 1st to 3rd etc. It can carry out with reference to the method described in.
  • a compound having a sulfonamide group can be produced by reacting a compound having an amino group with a reactive derivative of sulfonic acid as a raw material.
  • the reaction can be carried out with reference to, for example, the method described in the Chemical Society of Japan “Experimental Chemistry Course (4th edition)” 24 ⁇ (1992) (Maruzen).
  • a compound having a carpamate group can be produced by reacting a ⁇ compound having an amino group with a carbonate conductor as a raw material.
  • the reaction can be implemented by referring to the method described in “Chemical Experiment Course (4th edition)” volume 20 (1992) (Maruzen) edited by the Chemical Society of Japan.
  • a compound having a urea group can be obtained by reacting an amino group-containing compound with an isocyanate compound or aminocarbonyl halide.
  • a compound having a thiurea group can be obtained by reacting a compound having an amino group with a thioisocyanate compound or the like as a raw material.
  • reaction can be carried out with reference to, for example, the method described in the Chemical Society of Japan “Experimental Chemistry Course (4th edition)”, Volume 20 (1992) (Maru 'Zen). '
  • a compound having an ester group can be produced by reacting a compound having an alcohol group with a carboxylic derivative as a raw material.
  • the reaction can be carried out, for example, referring to “Chemical Experiment Course (4th edition)” edited by The Chemical Society of Japan, Volume 22 (1992) (Maruyoshi).
  • a compound having a secondary amine or a tertiary amine is obtained by reacting a compound having a secondary amino group or secondary amino group with a raw material as a raw material, and reacting with another alkylating agent or an epoxy compound.
  • the alkylating agent is preferably an organic sulfonate ester of an alkyl halide alcohol.
  • Reaction is carried out in a solvent inert to the reaction such as aromatic hydrocarbons, halogenated hydrocarbons, ethers, ketones such as acetone, 2-butanone, acetonitrile, acetate, DMF, DMA or NMP. To mix under-heating More done.
  • a solvent inert such as aromatic hydrocarbons, halogenated hydrocarbons, ethers, ketones such as acetone, 2-butanone, acetonitrile, acetate, DMF, DMA or NMP.
  • a compound having a secondary amine or a tertiary amine is used in the presence of a reducing agent such as sodium borohydride or sodium triacetoxyborohydride, or under catalytic reduction conditions such as palladium on carbon in a hydrogen atmosphere.
  • a reducing agent such as sodium borohydride or sodium triacetoxyborohydride
  • An alkyl group can be introduced by a reductive alkylation reaction with an aldehyde or a ketone using a compound having primary amine or secondary amine as a raw material.
  • a polystyrene resin carrying a reducing agent such as MP-triacetoxyborohydride.
  • a compound having a sulfonyl group or a sulfenyl group can be produced by an acid reaction of a compound having a sulfide group.
  • a compound having an adjacent diol can be produced by Os oxidation reaction of the corresponding olefin body. The reaction can be carried out, for example, by referring to the method described in “Chemical Experiment Course (4th edition)” edited by The Chemical Society of Japan, Volume 23 (1992) (Maruzen).
  • a compound having a primary alcohol group can be produced by a reduction reaction of a compound having a corresponding force loxyl group.
  • the reaction can be carried out, for example, by referring to the method described in 'Chemical Society of Japan “Experimental Chemistry Course (4th edition)” Volume 26 (1992) (Maruzen). 1
  • a corresponding agent can be produced by a catalytic reduction reaction using a compound having a double bond or a compound having a halogen group as a raw material.
  • the reaction is, for example, the Chemical Society of Japan “Experimental Chemistry Course (4th edition)” 26 ⁇ (1992) (Maruzen) It can carry out with reference to the method described in.
  • an alkoxypyridine, a compound having an aminoviridine skeleton can be produced by reacting an alkoxide, amine or the like using a corresponding compound having a black-and-white pyridyl group as a raw material. is there.
  • the reaction can be performed with reference to Step A of the second production method.
  • a compound having a cyanoaryl group can be produced by using a compound having a corresponding halogenated aryl group as a raw material and cross-coupling with zinc cyanide, etc. in the presence of a palladium catalyst. it can.
  • compounds having an alkenyl aryl group or an alkyl aryl group are based on a compound having a corresponding halogenated aryl group, and are cross-coupled with an organic tin reagent, boronic acid, etc. in the presence of a palladium catalyst.
  • the reaction can be carried out, for example, by referring to the method described in the Chemical Society of Japan “Experimental Chemistry Course (4th edition)” 25 ⁇ (1992) (Maruyo). .
  • a compound having a carboxylphenyl group is produced by reacting carbon dioxide with a lithium-halogen exchange reaction using alkyllithium, starting from a compound having a bromophenyl group. It is possible to The reaction can be carried out with reference to the method described in, for example, the Chemical Society of Japan “Experimental Chemistry Course (4th edition)” Volume 20 (1992) (Maruzen).
  • a compound having a carboxyl group or an amide group can be produced by hydrolyzing a compound having a corresponding ester group, amide group or chinano group.
  • the reaction can be carried out, for example, by the above-mentioned [Protective Groups in Organic Synthesis (third edition)] Edition) ”22 ⁇ (1992) (Maruzen) can be implemented with reference to the method described.
  • a compound having a cyano group can be produced by subjecting a compound having a corresponding carboxamide group to a dehydration reaction.
  • the reaction can be carried out, for example, by referring to the method described in the Chemical Society of Japan “Experimental Chemistry Course (4th Edition)” Volume 20 (1992) (Maruzen).
  • a polystyrene resin carrying a primary amine for the purpose of removing excess electrophilic reagents (acid chloride, sulphourel chloride, isocyanate, etc.) after completion of the reaction, such as PS-trisamine.
  • PS-Trisamine ArArgonaute Technologies Inc., USA
  • a strong cation exchange phase such as BoiidElut®SCX (Varian, USA)
  • BoiidElut®SCX Varian, USA
  • the raw material used for the production of the compound of the present invention can be produced, for example, by using a method described in Reference Examples described later, a known method, a method obvious to those skilled in the art, or a modified method thereof.
  • Z 2 represents halogen or —0—S0 2 CF 3.
  • L 2 represents hydrogen or methyl.
  • the ring of Q 1 has a nitrogen atom as a ring-constituting atom.
  • R 7 , R 8 and R 9 each have the same meaning as described above, and so on.
  • This step is a step for producing a compound (10) by carrying out a substitution reaction at the -tro group ortho position of the compound (8).
  • the substitution reaction in this step can be carried out in the same manner as in step 2 of the second production method.
  • the nitro compound (10) is reduced to produce the compound (la).
  • a reduction reaction of -tro group which can be usually employed by those skilled in the art can be used.
  • a reduction reaction using a reducing agent such as reduced iron or chlorotin, and a hydrogenated caro reaction using palladium-carbon, rhodium-carbon or the like as a catalyst can be mentioned.
  • the reaction can be carried out with reference to, for example, the method described in the Chemical Society of Japan “Experimental Chemistry Course (4th edition)” Volume 26 (1992) (Maruzen).
  • Two cyclic skeletons composed of a combination of the compound (1 1) and the compound (12) are preferably reacted in the presence of a transition metal catalyst and an appropriate additive to form a carbon-carbon bond.
  • a reaction to form A representative method is the method described in “Chemical Experiment Course (4th edition)” edited by The Chemical Society of Japan, 25 ⁇ (1992) (Maruzen).
  • the transition metal catalyst various palladium complexes such as tetrakis' (triphenylphosphine) palladium, various nickel complexes such as dibromobis (triphenylphosphine) nickel, and the like can be suitably used.
  • various ligands such as triphenylsphine, sodium carbonate, zinc and the like can be suitably used, but it is preferable to select appropriately according to the method to be applied. Usually, this reaction is carried out in a solvent at room temperature or under heating.
  • the nitro compound (13) is reduced to produce the compound (14).
  • the reduction of the ditro group in this step can be carried out in the same manner as in the step of raw material synthesis 1, but a reduction reaction using a reducing agent such as reduced iron or chlorotin tin is particularly suitable.
  • This step is a step for producing compound (b) by reducing the double bond of compound (14).
  • a double bond reduction reaction that can be usually employed by those skilled in the art can be used.
  • a contact angle reduction reaction using palladium-carbon or the like as a catalyst in a hydrogen atmosphere can be used.
  • Z 5 represents halogen or hydrogen
  • L 3 represents an amine protecting group.
  • the Q 2 and Q 3 each have the same meaning as described above. The same applies below. )
  • alkyllithium is allowed to act on compound (15) to produce aryllithium by lithium-halogen exchange or dehydrogenation reaction, followed by addition reaction to ketone to produce compound (16) It is a process.
  • the method described in “The Experiment Course (4th edition)” of the Chemical Society of Japan 25 ⁇ (1992) (Maruzen) or a method similar to it can be adopted.
  • This step is a method for producing the compound (17) by deprotecting the substituent L 3 on nitrogen of the compound (16).
  • conventional deprotection conditions corresponding to the substituent L 3 can be used.
  • the deprotection reaction of the amino group of I Protective Groups in Organic Synthesis (third edition) It is possible to apply the method described in.appel
  • This step is a method for producing an olefin body by subjecting compound (17) to a hydroxyl group elimination reaction.
  • the reaction can be carried out under basic conditions such as acid catalyzed dehydration, halogenation, and sulfonation.
  • the method described in “The Experimental Chemistry Course (Fourth Edition)” Volume 19 (1992) (Maruzen) or a method based on it can be used.
  • compound (lb) is produced by reducing the double bond of compound (18). Reduction reaction of this step can be carried out in the same manner as in Step C 2 of Starting Material Synthesis 2. .
  • D 3 from this step B 3 may be the corresponding replaced with each of the steps in accordance with its needs.
  • compounds from (16) mention may be made after the dehydration reaction in step C 3, deprotection of the nitrogen on a substituent L 3 in step B 3, how such reducing the double bond in step D 3 . (Raw material synthesis 4)
  • L 4 represents a carboxylic acid protecting group. The same shall apply hereinafter.
  • This step is a method for constructing a thiazole ring by reacting thioamide or thiourea with an ⁇ -haloketone represented by bromopyruvate or the like.
  • This step is a step of producing the carboxylic acid body (2a) by hydrolyzing the carboxylic acid ester body (20).
  • the reaction can be carried out using conventional hydrolysis conditions. If the ⁇ column is used, the method described in the deprotection reaction of the carboxyl group in I Protective Groups in Organic Synthesis (third edition) described in the eyes [] is applied. can do.
  • This process is represented by bromopyruvic acid, etc. for thioamide and thiourea.
  • the reaction can be carried out in the same manner as in Step Alpha 4 of raw material synthesis 4.
  • This step is a step for producing a compound (2 3) by carrying out a substitution reaction at the 2-position of thiazole of the compound (22).
  • the substitution reaction in this step can be carried out in the same manner as in Step 2 of the second production method.
  • This step is a step of producing the compound (2a) by hydrolyzing the carboxylic acid ester (23).
  • the hydrolysis reaction of this step can be carried out in the same manner as in Step B 4 of Starting Material Synthesis 4. .
  • This step is a method of constructing an oxazole ring by reacting amide and urea with a cr haloketone typified by bromopyruvate. Tui'chi edited by “Heterocyclic Compounds J vol. 4o” or Palmer edited by I Heterocyclic Compounds vol. 60 part A can be adopted. Process B 7 >
  • This step is a step of producing the compound (2b) by hydrolyzing the carboxylic acid ester (25).
  • the hydrolysis reaction of this step the feed synthesis 4 steps: B 4 and may be carried out in a similar manner.
  • This step is a step for carrying out an amidation reaction from the compound (26) and the compound (27).
  • the reaction is in accordance with step 1 of the first production method.
  • the Chemical Society of Japan “Experimental Chemistry Course (4th edition)” Vol. 22 (1992) (Maruzen) or the above (“Compendium of Organic Synthetic Methods” Can be implemented with reference to the methods described in Volumes 1 to 3 etc.
  • This step is a method for constructing an oxazoline ring by subjecting compound (28) to a dehydration cyclization reaction.
  • compound (28) for example, Phillips, AJ; Wipf, R; Williams, DR; et al., Org Lett, 2000, 2 (8), 1165-1168, or the above-mentioned “: Heterocyclic Compoundsj”
  • the method described in Volume 60 partA, partB, etc. can be implemented as a reference.
  • This step is a method for constructing an oxazole ring by carrying out an oxidation reaction from the compound (29).
  • an oxidation reaction for example, Phillips, AJ; Wipf, P .; Williams, DR; et al., Org Lett, 2000, 2 (8), 1165-1168, or “The method described in Heterocyclic Compounds J Vol. 60 partA can be used as a reference.
  • This step is a step of producing the compound (2 c) by hydrolyzing the carboxylic acid ester (30).
  • the hydrolysis reaction of this step can be carried out in the same manner as in Step B 4 of Starting Material Synthesis 4.
  • Ar represents an optionally substituted aryl or an optionally substituted heteroaryl, and is bonded to an oxazole ring at a carbon atom on the ring.
  • Z 3 and Z 4 are respectively The meaning is the same as above.
  • This step is a method of synthesizing a biaryl compound from compound (3 1) and compound (3 2).
  • the reaction in this step can be performed according to the method described in, for example, HODGETTS, KJ; KERSHAW, MT; Org Lett, 2002, 4 (17), 2905-2907. Step B. 9 >
  • This step is a step of producing the compound (2 d) by hydrolyzing the carboxylic acid ester (3 3).
  • the hydrolysis reaction of this step can be carried out in the same manner as in Step B 4 of Starting Material Synthesis 4.
  • the substituent bonded to the compound (I) of the present invention can be converted to an appropriate time in the above step to proceed to the next step.
  • a conversion method for example, in the raw material synthesis 3, a Boc group is introduced at the position of R 9 and, at an appropriate time, before step B 3 , before step C 3 , or before step D 3 .
  • Examples thereof include a method in which after deprotecting the Boc group, an alkylation reaction is performed to convert it into the partial structure R 9 of the compound according to the present invention.
  • reaction products obtained by the above production methods can be isolated and purified as various solvates such as a free compound, a salt thereof, or a hydrate.
  • the salt can be produced by subjecting it to normal salt formation treatment.
  • Isolation and purification can be performed by applying ordinary chemical operations such as extraction, concentration, distillation, crystallization, filtration, recrystallization, and various chromatographic methods. '
  • optical isomers can be isolated by conventional methods utilizing physicochemical differences between isomers.
  • optical isomers can be separated by a general optical resolution method such as fractional crystallization or chromatography.
  • An optically different 1 "organism can also be produced from a suitable optically active raw material compound.
  • Nerve growth factor receptor inhibitory activity was measured using a ligand-dependent increase in intracellular calcium concentration as an index.
  • HEK293 cells stably expressing human nerve growth factor receptor (American-type 'Kartiyaichi' Collection)
  • the medium is loaded with a buffering buffer (fluorescent labeling reagent (trade name: Fluo4-AM, Dojindo), 1.5 ⁇ ⁇ washing solution: Hank's balanced salt solution (HBSS), 20 mM 2- [4- (2-hydroxyethyl) -1-Piperazinyl] ethanesulfonic acid (HEPES)-Sodium hydroxide (NaOH), 2.5 mM probenecid, 0.1% ushi serum albumin
  • HBSS Hank's balanced salt solution
  • HEPES 2- [4- (2-hydroxyethyl) -1-Piperazinyl] ethanesulfonic acid
  • NaOH sodium hydroxide
  • probenecid 0.1% ushi serum albumin
  • BSA blood pressure
  • ELx405, Bio-Tech (BIO-TEK) Instruments a plate washer
  • NGF nerve growth factor
  • the concentration that inhibits 50% was calculated as the 'IC 50 value when the NGF addition was 0% and the response at the time of buffer addition was 100%.
  • the results are shown in Table 1 below.
  • Ex represents the compound number of Examples described later. As a result of this test, it was confirmed that the compound of the present invention has a nerve growth factor receptor inhibitory action.
  • CPA cyclophosphamide
  • the total urination weight was divided by the total urination frequency to calculate the effective bladder capacity.
  • the rate of change in effective bladder capacity due to compound administration was calculated assuming that the value before compound administration was 100%.
  • Table 3 The results are shown in Table 3 below.
  • the effective bladder capacity decreased (about 0.5 ml) 2 days after CPA treatment, and frequent urination was observed.
  • the compound of the present invention improved the frequent urination state well.
  • Example 4 92 increased the effective bladder capacity to 177%.
  • 1% acetic acid (99% distilled water) was intraperitoneally administered to male Wistar rats (Charles Lipper), and the number of writhing was measured 10 to 20 minutes after administration.
  • the compound (10 mg / 5 ml / kg) or solvent (0.5% methylcellulose solution) was orally administered 5 minutes before administration of 1% acetic acid. Taking the writhing frequency of the solvent administration group as 100%, the writhing frequency suppression rate by compound administration was calculated. The results are shown in Table 4 below. In this test, the compound of the present invention showed excellent analgesic action. [Table 4]
  • the compound of the present invention has a potent trkA receptor inhibitory activity in vitro and in vivo, and has an effect of improving urination symptoms and an analgesic effect. Therefore, the compound of the present invention can be expected as an excellent therapeutic or prophylactic agent for various lower urinary tract diseases accompanied by urination symptoms and various pain diseases.
  • a pharmaceutical composition containing the compound (I) of the present invention or a salt thereof as an active ingredient is usually prepared using a carrier, an excipient, and other additives used for formulation.
  • Administration is oral via tablets, pills, capsules, granules, powders, liquids, etc., or parenteral via intravenous, intramuscular injections, suppositories, transdermal, nasal or inhalation. Either form may be used.
  • the dose is appropriately determined depending on the individual case, taking into account the symptoms, age of the subject, sex, etc., but usually for oral administration, it is about 0.001 mg / kg to 100 mg / kg per day for an adult. Do this once, or in 2-4 divided doses.
  • the solid composition for oral administration when administered intravenously depending on symptoms, it is usually administered once to multiple doses in the range of 0.0001 mg / k to 10 mg / kg per adult. In the case of inhalation, it is usually administered once or multiple times in a range of 0.0001 mg / kg to 1 mg / kg per adult.
  • the solid composition for oral administration tablets, powders, granules and the like are used.
  • one or more active substances may contain at least one inert excipient such as lactose, mannitol, pudou sugar, hydroxypropylcellulose, microcrystalline cellulose, starch. , Mixed with polyvinylpyrrolidone, magnesium aluminate metasilicate and the like.
  • composition is prepared according to conventional methods and with inert additives such as magnesium stearate. It may contain lubricants such as mulch, disintegrating agents such as sodium carboxymethyl starch, and solubilizing agents. If necessary, tablets or pills may be coated with sugar coating, gastric or enteric coating agent.
  • inert additives such as magnesium stearate. It may contain lubricants such as mulch, disintegrating agents such as sodium carboxymethyl starch, and solubilizing agents. If necessary, tablets or pills may be coated with sugar coating, gastric or enteric coating agent.
  • Liquid compositions for oral administration include pharmaceutically acceptable emulsions, solutions, suspensions, syrups, elixirs, etc., and include generally used inert solvents such as purified water and ethanol. Including. In addition to the inert solvent, this composition may contain auxiliary agents such as a solubilizing agent, a wetting agent, and a suspending agent, a sweetening agent, a corrigent, an aromatic, and a preservative.
  • auxiliary agents such as a solubilizing agent, a wetting agent, and a suspending agent, a sweetening agent, a corrigent, an aromatic, and a preservative.
  • Injections for parenteral administration include sterile aqueous or non-aqueous solutions, suspensions, and emulsions.
  • aqueous solvent include distilled water for injection and physiological saline.
  • Non-aqueous solvents include, for example, propylene glycol, polyethylene glycol, vegetable oils such as olive oil, alcohols such as ethanol, polysorbate 80 (Pharmacopeia name), and the like.
  • Such a composition may further contain a tonicity agent, a preservative, a wetting agent, an emulsifier, a dispersant, a stabilizer, and a solubilizing agent.
  • These are sterilized by, for example, filtration through a bacteria-retaining filter, blending with a bactericide or irradiation.
  • these can be used by preparing a sterile solid composition and dissolving and suspending it in sterile water or a sterile solvent for injection before use.
  • Transmucosal agents such as inhalants and nasal agents are used in solid, liquid or semi-solid form, and can be produced according to conventionally known methods.
  • excipients such as ratatose starch, and further pH adjusters, preservatives, surfactants, lubricants, stabilizers, thickeners and the like may be added as appropriate.
  • an appropriate device for inhalation or insufflation can be used.
  • the compound may be administered alone or as a powder in a formulated mixture, or as a solution or suspension in combination with a pharmaceutically acceptable carrier. can do.
  • the dry powder inhaler or the like may be for single or multiple administration, and a dry powder or a powder-containing capsule can be used.
  • a suitable propellant such as black mouth fluoroalkane, It may be in the form of a pressurized aerosol spray using a suitable gas such as drofluoroalkane or carbon dioxide.
  • a low melting wax such as a mixture of fatty acid daricelide or cocoa butter is melted, the active ingredient is added and evenly dispersed by stirring. Then pour into a suitable mold and cool and solidify.
  • Liquid formulations include solutions, suspensions, retention enemas and emulsions such as water or aqueous propylene glycol solutions.
  • the compound of the present invention will be described more specifically with reference to Examples.
  • the production method of the raw material compound is described as a reference example.
  • the manufacturing method of this invention compound is not limited only to the manufacturing method of the specific Example shown below, It can manufacture also with the combination of these manufacturing methods, or a known manufacturing method.
  • 2,4-Difluoro-6-nitrotropenol was reacted with trifluoromethanesulfonic anhydride in pyridine to produce 2,4-difluoro-6-nitrophenyl trifluoromethanesulfonate.
  • 1,2,3-Trifluo-Piet 4-Nitrobenzene is allowed to react with power hydroxide and cyanoacetate ester in DMSO and then with acetic acid and hydrochloric acid (2,3-Difluo-Pe-4 -Nitrophenyl) acetonitrile was prepared.
  • 3-Chloro-2,6-difluorophenylacetonitrile was reacted with tetramethylammonium nitrate and trifluoromethanesulfonic anhydride in salt methylene chloride (3-Chloro-2,6- Difluoro-5-nitrophenyl) acetonitrile was prepared.
  • 4-Cyan-4-hydroxyzepane-1-carboxylic acid tert-butyl ester was prepared by reacting 4-oxozepan-1-carboxylic acid tert-butyl ester with sodium cyanide in aqueous sodium hydrogen sulfite solution.
  • 4-Hydroxyzepan-4-power rubinoic acid methinoreester hydrochloride was prepared by allowing 10% hydrogen chloride / methanol to react with 4-cyan-4-hydro'xyzepan-1-carboxylic acid tert-butyl ester .
  • 2- [4- (5-Fluoro-2-2-trophenyl) piperazine can be obtained by allowing 2-piperazine-1-ylacetamide and triethylamine to react with 2,4-difunoleolonitrobenzene in acetonitrile. -1-yl] acetamide was produced.
  • 4-oxozepan-1-canolevonic acid tert-butyl ester is reacted with lithium diisopropylamide and 1,1,1-trifluoro-N-phenyl-N-[(trifluoromethyl) sulfonyl] methanesulfonamide in THF In this way, 4- ⁇ [(trifluoromethyl) sulfonyl] oxo ⁇ -2,3,6,7-tetrahydro-1H-azepine-1-force norevonic acid tert-butyl ester was produced.
  • Tetrafluoroborate bis (pyridine) 3udonium was allowed to act on (4-aminophenyl) acetonitrile in methylene chloride to produce (4-amino-3-benzophenole) acetonitrile.
  • Reference example 1 3 5 2-funoleo-or 6-dinitrophene trifluoromethanesulfonate ester in DMF [ ⁇ , ⁇ -bis (diphenylphosphino) phenocene] -diclonal palladium (11), potassium phosphate, 4 -(4,4,5,5-Tetramethyl-1,3,2-dioxaborolane-2-yl) -3,6-dihydropyridine-1 (2 ⁇ ) -carboxylic acid tert-butyl ester (2_fluor mouth-6-nitrophenol) -3,6-dihydropyridine
  • Reference example 1 7 5 2- [4- (4-Formino 2-ditropenyl) piperazine-1-yl] acetamide is treated with DM-toxylphosphoryl acetic acid ethyl ester, carbonated rheme (2E) -3- ⁇ 4 -[4- (2-Amino-2-oxoethyl) piperazine-1-yl] -3 ⁇ -trophenyl-2-acrylinolic acid ethyl ester was prepared.
  • Reference Example 1 7 6 "
  • N- (2-Promopyridin-3-yl) -2,2,2-trifluoroacetamide was prepared by reacting 2-bromopyridine-3-amine with trifluoroacetic anhydride in THF.
  • Methyllithium and butyllithium are added to THF solution of N- (2-promophenyl) -2,2,2-trifluoroacetamide, followed by 4-year-old xo-1-piperidine power norlevonic acid tert-butyl ester
  • 4-hydroxy-4- [2-[(trifluoroacetyl) amino] phenyl] -1-piperidinecarboxylic acid tert-butyl ester was produced.
  • Reference example 3 4Hydroxy-4- ⁇ 2-[(trifluoroacetyl) amino] phenyl ⁇ -1-piberidinecarboxylic acid tert-butyl ester in THF-methanol solution treated with 15% aqueous sodium hydroxide solution 4 Tert-Ptylester of-(2-aminophenol) -4-hydroxy-1-piperidine strength ruponate was prepared.
  • 5-Fluoro-2- (1-, 2,3,6-tetrahydro-4-pyridinyl) aniline dihydrochloride in pyridine solution was allowed to react with 4-morpholine carboyl chloride to give 5-fluoro-2- [1- (4-morpholinylcarbonyl) -1,2,3,6-tetrahydro-4-pyridinyl] aniline was prepared.
  • 4-Hydroxy-2-methylbutanamide was produced by allowing ammonia water to act on 3-methyldihydrofuran-2 (3H) -one.
  • Triethylamine and 4-dimethylaminopyridine were added to a dichloromethane solution of 2-methylbutanamide, and then benzoyl chloride was allowed to act to produce 4-amino-3-methyl-4-oxobutylbenzoate.
  • 6-Methoxypyridazine-3-carbothiolamide was prepared by adding a 4M salt hydrogen / EtOAc solution to 6-methoxypyridazine-3-carbonitryl and then reacting with dithiophosphoric acid 0,0-jetyl ester. .
  • 2- (3-Furyl) -1,3-thiazole-4-carboxylic acid ethyl ester was prepared by allowing ethenole 3-bromo-2-oxobutanoic acid ethyl ester to react with furan-3-force norevothamide in ethanol. .
  • Tetrahydro-2H-pyran-4-carbothioamide was allowed to react with 3-bromo-2-oxopropanoic acid ethyl ester in ethanol.
  • the reaction solution was concentrated to give a 1,2-dimethoxetane solution, which was then treated with pyridine and trifluoroacetic anhydride to give 2- (tetrahydro-2H-pyran-4-yl) -1,3-thiazolecarboxylic acid ester.
  • a chill ester was produced.
  • (2S) -3-Hydroxy-2-[(pyridazine-4-ylcarponyl) amino] propionic acid methyl ester is prepared by reacting 4-pyridazinecarboxylic acid chloride with L-serine methyl hydrochloride and triethylamine in acetonitrile. did.
  • REx in the left column of the table indicates the reference example number, and the structural formula of the reference example compound is described in the Str column in the middle column.
  • the structural formula with * in the column of the table indicates that the compound is optically active.
  • reference example numbers that refer to the manufacturing method as Syn are shown. For example, in the manufacturing method described as “2 7 ⁇ 1 4”, the same manufacturing method as the reference example of 27 is performed, and then the same manufacturing method as the reference example of 14 is performed.
  • (Sal) described on the right side of Syn means a salt, and a compound not described indicates a free form.
  • Example 1 202 described in Tables 6 to 68 can be produced by the same method with reference to any of the production methods of the following representative examples. The number is shown as Syn in the table. .
  • N- [2- (amino force carbonyl) -6- (4-methylpiperazine-1-yl) phenyl] -2-phenyl-1,3-thiazole-4-carboxamide 10.0 ml of sulfuric acid was added. Under ice cooling, a solution of 310 mg of sodium nitrite in 3.00 ml of ice was added to this, and then stirred at room temperature for 5 hours. Water was added to the reaction mixture, and the mixture was extracted with Kokuguchi Form. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • trans-1-benzyl-4- (2- ⁇ [(2-phenyl-1,3- 2.35 g of methyl ester hydrochloride of thiazol-4-yl) carbonyl] amino ⁇ phenyl) pyrrolidine-3-canoleponate was prepared.
  • reaction mixture was concentrated under reduced pressure, and the resulting residue was washed with ethanol and washed with N- ⁇ 2- [4- (2-amino-2-oxoethyl) piperazine-1-yl] phenylene ⁇ -2- ( 6-oxo-1,6-dihydropyridine-3-inole) -1,3-thiazole-4-carboxamide hydrobromide 123 mg was prepared.
  • 2-morpholine-4-yl-N- (2-piperazine-1-ylphenyl) -1,3-thiazole-4-carboxamide hydrochloride 600 mg of acetonitrile with 10.0 ml suspension of acetic acid 25.0 ⁇ 1, tetrahydro-pyran -293 mg of 4-one and 1.55 g of sodium triacetate chloropide were added and stirred at room temperature for 7 days. A saturated aqueous sodium hydrogen carbonate solution was added to the reaction solution, and the resulting insoluble material was collected by filtration and washed with acetonitrile.
  • Example 2 8 1 ′ ′ l- (5-Bromo-3- ⁇ [(2-morpholine-4-yl-1,3-thiazol-4-yl) carbonino]] amino) pyridine-2- ⁇ ) Piperidine-4-carboxamide Add 195mg DMF 1.95ml solution 33.0mg sodium acetate, acrylonitrile 50 ⁇ 1 tri- ⁇ -trilphosphine 9.0mg, palladium acetate 9.0mg and irradiate with microwave at 200 ° C For 10 minutes. Water was added to the reaction mixture, and the mixture was extracted with EtOAc. The organic layer was washed with saturated brine. The organic layer was dried over magnesium sulfate, and the solvent was distilled off under reduced pressure.
  • N- ⁇ 2- [4- (2-Amino-2-oxoethyl) piperazine-1-yl] phenyl ⁇ -2-bromo-1,3-thiazole-4-carboxamide 300 mg was dissolved in 20 ml dioxane. To this, 380 ⁇ l of (2-methoxyethyl) methylamine was added dropwise at room temperature, and the mixture was stirred at 100 ° C. for 3 days. To the reaction solution was added aqueous sodium hydrogen carbonate solution, extracted with chloroform, and dried over magnesium sulfate. The residue obtained by removing the solvent under reduced pressure was purified by silica gel column chromatography (chlorophore / rem: methanol 50: 1).
  • ru-1,3-oxazole-4-carboxamide 150mg in methanol 8.00ml 10% palladium-carbon 20.0mg was added and stirred for 15 hours under hydrogen atmosphere.
  • the reaction solution was filtered through Celite, and the residue obtained by concentrating the mother liquor was recrystallized from ethanol to give N- ⁇ 5- [4- (2-amino-2-oxoethyl) piperazine-1-inole. ] 85.0 mg of -1-methyl-1H-pyrazol-4-yl ⁇ -2-morpholin-4-yl-1,3-oxazole-4-carboxamide was produced.
  • N- ⁇ 2- [4- (2-Amino-2-oxoethyl) -1-piperajuryl] fenoline ⁇ -2- (2-Mouth -4-pyridinyl) -1,3-thiazole -4 -86 mg of sodium alumide was added to 1.5 ml of DMSO in 1.5 mg of DMLP in 150 mg of viruxamide, and the mixture was stirred at 90 ° C for 2 hours and 120 ° C for 24 hours. Water was added to the resulting mixture and stirred for a while, and then the precipitate was collected, filtered and dried.
  • the residue was purified using preparative TLC, and then reacted with a 4M hydrochloric acid-hydrogen ZEtOAc solution in a mixed solution of methanol and chloroform.
  • the solution was concentrated, and the resulting residue was washed with a mixed solvent of ethanol and isopropyl ether and dried under reduced pressure to obtain a mixture of the two compounds.
  • This was neutralized with a saturated aqueous solution of sodium hydrogen carbonate and extracted with black mouth form.
  • the organic layer was washed with saturated brine, dried over magnesium sulfate, concentrated, and separated using preparative TLC. The upper fraction was washed with a mixed solvent of ethanol and isopropyl ether.
  • the lower fraction was dissolved in ethyl acetate, reacted with a 4M hydrochloric acid-hydrogen / EtOAc solution, and then washed with a mixed solvent of ethanol and isopropyl ether.
  • N- ⁇ 2- [4- (2-Amino-2-oxoethyl) piperazine-1-yl] phenyl ⁇ -2-piperazine-1-yl-1,3-thiazole-4-power lupoxamide 155 mg and propionaldehyde 26 ⁇ 1 were suspended in 2 ml of methylene chloride, 62 ⁇ 1 of acetic acid was added, and the mixture was stirred at room temperature for 1 hour. Sodium triacetoxypolohydride 76 mg was added, and the mixture was further stirred for 15 minutes. Aqueous sodium hydrogen carbonate solution was added to the reaction mixture, and the mixture was extracted with chloroform. The solvent was distilled off under reduced pressure.
  • a solution of 1.85 ml of DMA containing 524 mg of 1-carboxylic acid tert-butyl ester and 0.76 ml of ethyldiisopropylamine was stirred at 100 ° C. overnight.
  • 200 ml of water was added and extracted with black mouth form.
  • a microwave solution was irradiated at 200 ° C for 30 minutes to a solution of 47.2 mg of tert-butyl ester rubonic acid and 0.5 ml of 1-methyl-2-pyrrolidone in 0.041 ml of ethyldisopropylamine. 100 ml of water was added to the mixture, and the mixture was extracted with throat form. The organic layer was dried over magnesium sulfate and concentrated under reduced pressure.
  • Example 1 0 0 1 to 1 in the same manner as Example 1 0 2 9 from 1-fluoro-2-nitrobenzene, 2-phenyl-1,3-thiazole-4-carboxylic acid and the corresponding raw materials 0 4 4 compounds were prepared.
  • Example 1 0 45 to 1 0 5 2 were prepared in the same manner as Example 1 0 4 8 from 1- (2-aminophenyl) piperidine-4-carboxylic acid ethyl ester and the corresponding raw materials. .
  • Example 1 in the same manner as Example 1 0 6 5 from 2-phenol-N- (2-piperidine-4-ylphenyl) -1,3-thiazolene-4-carboxamide and the corresponding raw materials Compounds from 0 5 3 to 1 0 9 1 were prepared.
  • Example 1 1 1 6 Using the corresponding carboxylic acid as a raw material, the same compounds as in Example 1 1 1 6: L 1 6 1 were produced in the same manner as in Example 1 1 1 6.
  • Examples 1 1 6 2 to 1 1 7 7 were produced in the same manner as in Example 1 1 6 2 using the corresponding aldehyde as a raw material.
  • Example 1 1 7 8 ′ Methanesulfuryl chloride 3.4 mg to N- ⁇ 2- [4- (2-amino-2-oxoethyl) piperazine-1-inole] phenol-))-2-piperidine-4 -Yle-1,3-thiazole-4-carboxamide dihydrochloride 12.5 mg and triethylamine 10.4 ⁇ in 0.50 ml of dichlore ethane and 0.50 ml of ⁇ , ⁇ -dimethylformamide at room temperature Add Stir overnight. Add PS-Isocyanate (Argonaute Technology) 50 mg and PS-Trisamine (Argonaute Technology) 50 mg to the reaction mixture at room temperature for 4 hours. Stir and filter insolubles.
  • Example 1 1 78 In the same manner as in Example 1 1 78, using the corresponding sulfoelk mouthlid as the starting material, the compounds of Examples 1 1 78 to L 1 9 5 were produced.
  • Example 1 1 96 using the corresponding isocyanate or isothiocyanate as a raw material, the compounds of Examples 1 1 96 to 120 2 were produced. .
  • the compound of the present invention has a potent trkA receptor inhibitory action, and is accompanied by frequent urination, urgency, urinary incontinence, lower urinary tract pain, and pain associated with various lower urinary tract diseases including drugs, particularly overactive bladder It is useful as a therapeutic agent for various diseases.

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Abstract

[PROBLÈMES] Proposer un agent thérapeutique ou prophylactique contre une miction fréquente/une forte envie d'uriner ou une incontinence associée à une vessie hyperactive, une maladie des voies urinaires inférieures accompagnée d'une douleur des voies urinaires inférieures telle que la cystite interstitielle et la prostatite chronique ou une maladie accompagnée d'une douleur qui agit sur la base d'une excellente activité inhibant les récepteurs trkA. [Moyens pour RÉSOUDRE les PROBLÈMES] L'invention concerne un nouveau dérivé d'azolecarboxamide ayant un cycle azole (par exemple, un cycle thiazole ou oxazole) lié à un noyau benzène, pyridine ou pyrimidine par l'intermédiaire d'un carboxamide. Il est confirmé que le dérivé d'azolecarboxamide a une activité puissante d'inhibition des récepteurs trkA. Il est trouvé que le dérivé d'azolecarboxamide peut être utilisé comme agent thérapeutique ou prophylactique très efficace, sans danger, en cas de maladie des voies urinaires inférieures ou de maladie accompagnée d'une douleur.
PCT/JP2007/059009 2006-04-19 2007-04-19 DÉRIVÉ d'azolecarboxamide WO2007123269A1 (fr)

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JP2008512196A JP5182088B2 (ja) 2006-04-19 2007-04-19 アゾールカルボキサミド誘導体
MX2008013400A MX2008013400A (es) 2006-04-19 2007-04-19 Derivado de azolcarboxamida.
US12/297,275 US8163746B2 (en) 2006-04-19 2007-04-19 Azolecarboxamide derivative
CN2007800140537A CN101426774B (zh) 2006-04-19 2007-04-19 唑类甲酰胺衍生物
CA2649043A CA2649043C (fr) 2006-04-19 2007-04-19 Derive d'azolecarboxamide

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